Transforming growth factor-beta receptor kinase (TGF-β) denotes a family of proteins, TGF-β1, TGF-β2, and TGF-β3, which are pleiotropic modulators of cell growth and differentiation, embryonic and bone development, extracellular matrix formation, hematopoiesis, immune and inflammatory responses (Roberts and Sporn Handbook of Experimental Pharmacology (1990) 95:419–58; Massague et al. Ann Rev Cell Biol (1990) 6:597–646). Other members of this superfamily include activin, inhibin, bone morphogenic protein, and Mullerian inhibiting substance. TGF-β initiates an intracellular signaling pathway leading ultimately to the expression of genes that regulate the cell cycle, control proliferative responses, or relate to extracellular matrix proteins that mediate outside-in cell signaling, cell adhesion, migration and intercellular communication.
Therefore, inhibitors of the TGF-β intracellular signaling pathway are useful treatments for fibroproliferative diseases. Specifically, fibroproliferative diseases include kidney disorders associated with unregulated TGF-β activity and excessive fibrosis including glomerulonephritis (GN), such as mesangial proliferative GN, immune GN, and crescentic GN. Other renal conditions include diabetic nephropathy, renal interstitial fibrosis, renal fibrosis in transplant patients receiving cyclosporin, and HIV-associated nephropathy. Collagen vascular disorders include progressive systemic sclerosis, polymyositis, scleroderma, dermatomyositis, eosinophilic fascitis, morphea, or those associated with the occurrence of Raynaud's syndrome. Lung fibroses resulting from excessive TGF-β activity include adult respiratory distress syndrome, idiopathic pulmonary fibrosis, and interstitial pulmonary fibrosis often associated with autoimmune disorders, such as systemic lupus erythematosus and scleroderma, chemical contact, or allergies. Another autoimmune disorder associated with fibroproliferative characteristics is rheumatoid arthritis.
Eye diseases associated with a fibroproliferative condition include retinal reattachment surgery accompanying proliferative vitreoretinopathy, cataract extraction with intraocular lens implantation, and post glaucoma drainage surgery.
PCT applications WO98/06715, WO98/07425, and WO 96/40143, all of which are incorporated herein by reference, describe compounds which are either imidazoles or are indoles substituted at the 3- or 4-position with a piperazine ring linked through a carboxamide linkage. Additional compounds which are conjugates of piperazines with indoles are described as insecticides in WO97/26252, also incorporated herein by reference.
The compounds of the invention are quinazoline derivatives. Other quinazoline compounds for other uses have been described. U.S. Pat. No. 5,721,237 assigned to Rhone-Poulenc Rorer is directed to methods for selective treatment of cell growth and differentiation characterized by activity of human epidermal growth factor (EGF) receptor type II using quinazoline substituted only in the 4-position with an aromatic moiety optionally coupled to the quinazoline through a linking moiety. U.S. Pat. No. 4,480,883 describes compounds that exhibit tyrosine kinase inhibition activity wherein the heterocyclic portion of a quinazoline or other fused ring nitrogen-containing aromatic system is substituted only once with an aromatic moiety, again optionally coupled through a linker. U.S. Pat. No. 5,616,582 assigned to Zeneca describes tyrosine kinase inhibitors which are quinazolines linked through an amino group at the 4-position to a substituted or unsubstituted phenyl. These compounds contain no substituents at position 2. U.S. Pat. No. 5,475,001 also assigned to Zeneca describes similar compounds with the same activity. U.S. Pat. No. 5,430,148 assigned to Agouron Pharmaceutical describes antiproliferative substituted quinazolinones and their counterparts wherein the keto group is replaced by a sulfone.
U.S. Pat. No. 5,719,157 to Takeda Chemical Industries describes pharmaceutical compositions for inhibiting bone resorption which include 4-phenyl quinoline derivatives which may further be substituted at the 2-position with an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.
U.S. Pat. No. 5,034,393 issued to Hackler et al. describes fungicides encompassing a genus of pyridopyrimidine, pteridine, pyrimidopyrimidine, pyrimidopyridazine, and pyrimidotriazine derivatives.
None of the foregoing patents describes quinazoline derivatives which specifically inhibit TGF-β.
U.S. Pat. No. 6,184,226 assigned to the assignee of the present application, Scios Inc., describes compounds and methods of inhibiting p38 kinase activity using substituted quinazolines or quinazoline derivatives having an N in the quinazoline backbone at the 8-position. These compounds include an N-containing substituent at the 1-position that links the quinazoline or derivative thereof to an optionally substituted phenyl, pyridyl, indolyl, or pyrimidinyl group. PCT application WO 00/12497, also assigned to the assignee of the present application, Scios Inc., describes compounds and methods of inhibiting p38-α and TGF-β using substituted quinazolines or quinazoline derivatives wherein up to two N's replace up to two C's at the 5-position to the 8-position in the quinazoline backbone. These compounds include a linker at the 1-position that links the quinazoline or derivative thereof to an optionally substituted cyclic aliphatic cyclic heteroaliphatic, aromatic or heteroaromatic group. These compounds also include an optionally substituted non-interfering substituent at the 2-position. There is no indication which species in this genus of compounds have a particularly high TGF-β inhibition activity, which species have a selective activity for TGF-β inhibition over p38, nor which species have suppressed epidermal growth factor (EGF) receptor tyrosine kinase activity, which EGF receptor tyrosine kinase activity has been associated with quinazolines and derivatives thereof, see e.g., U.S. Pat. No. 6,251,912. As kinases have similar domains, it would be useful to have compounds with greater selectivity for TGF-β, preferably with greater selectivity over p38 or EGF receptor.